Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.N[C@@H:4]1[CH2:9][CH:8]2[CH2:10][CH2:11][N:5]1[CH2:6][CH2:7]2.C([N:14](CC)CC)C.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[S:30][C:29]([C:31](Cl)=[O:32])=[CH:28][CH:27]=2)[C:22]=1[CH3:34]>ClCCl>[N:5]12[CH2:11][CH2:10][CH:8]([CH2:7][CH2:6]1)[C@H:9]([NH:14][C:31]([C:29]1[S:30][C:26]([C:23]3[C:22]([CH3:34])=[C:21]([C:20]([F:36])([F:35])[F:19])[O:25][N:24]=3)=[CH:27][CH:28]=1)=[O:32])[CH2:4]2
Reactant: N[C@@H]1CC2CCN1CC2
Reactant: CCN(CC)CC
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccc(C(=O)N[C@@H]3CN4CCC3CC4)s2)noc1C(F)(F)F
Reaction time: 20 h
Yield: 39.4 %

Procedure:
A suspension of (S)-(−)-aminoquinuclidine dihydrochloride (55 mg, 0.275 mmol) in dichloromethane (1 mL) as treated with triethylamine (53 μL, 0.55 mmol) followed by 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol) and the reaction mixture allowed to stir for 20 hr. After this time, the reaction mixture was evaporated and the residue partitioned between EtOAc (5 mL) and a 1 N HCl solution (10 mL). The aqueous portion was then basified to pH˜10-12 with a 1N NaOH solution. The aqueous portion was then extracted with EtOAc (10 mL) which was then washed with a brine solution (10 mL), dried over MgSO4, filtered, and evaporated in vacuo to afford product as a colorless solid (38 mg, 40%). 1H NMR (CDCl3) 1.50-1.62 (m, 1H), 1.70-1.88 (m, 3H), 2.08-2.12 (m, 2H), 2.37 (d, J=1.3, 3H), 2.72-3.10 (m, 5H), 3.44 (ddd, J=14.0, 9.7, 2.2, 1H), 4.14-4.22 (m, 1H), 6.56 (br d, J=7.0, 1H), 7.49 (d, J=4.0, 1H), 7.56 (d, J=4.0, 1H). 19F NMR −63.13. LC/MS 4.63 min, [M+1]+386.
Reaction SMILES: B(Cl)(Cl)Cl.[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.[Cl:16][CH2:17][C:18]#N.[Cl-].[Al+3].[Cl-].[Cl-].[OH2:24]>C(Cl)Cl>[NH2:15][C:13]1[C:12]([C:18](=[O:24])[CH2:17][Cl:16])=[CH:11][C:10]2[O:5][CH2:6][CH2:7][O:8][C:9]=2[CH:14]=1
Reactant: N#CCCl
Reactant: O
Reactant: Nc1ccc2c(c1)OCCO2
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Nc1cc2c(cc1C(=O)CCl)OCCO2
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 1 M boron trichloride in methylene chloride (4 L, 4.00 mol). The solution is cooled to -20° C., then 1,4-benzodioxane-6-amine (500 g, 3.31 mol) available from the Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, is added as a solution in methylene chloride (250 mL) over 30 min. The temperature increases to 10° C. during the addition and is subsequently re-cooled back to -10° C. Chloroacetonitrile (250 mL, 3.95 mol) is added over 5 min, followed by addition of aluminum chloride (485 g, 3.64 mol). The resulting dark mixture is heated at reflux for 24 h. The reaction mixture is cooled to ambient temperature and transferred to two 20-L separatory funnels, each containing 10 L of water. After being stirred for 2.5 h, the organic layer is separated and the aqueous layer is extracted with methylene chloride (4×4 L). The combined organic layers are washed with brine (4 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The resultant thick brown slurry is successively treated with 600 mL of methylene chloride and 2 L of hexane. The mixture is stirred at 0° C. for 30 min. The precipitate is collected by filtration on a Buchner funnel, washed with hexane (1 L) and dried in vacuo. at 30° C. yielding 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone as a yellow powder. Reverse HPLC (Spherisorb ODS-25 micron, 1:1 MeCN-H2O) indicated a purity of 91%. Recrystallization from CH2Cl2 provides an analytical sample as a yellow crystalline solid: mp 130° C. (dec.). 1H NMR (CDCl3, 200 MHz) δ4.24 (m, 2H), 4.32 (m, 2H), 4.59 (s, 2H), 6.21 (s, 1H), 6.23 (br. s, 2H), 7.29 (s, 1H). Elemental analysis: Calculated for C10H10ClNO3 : C 52.76, H 4.43, N 6.15. Found: C 52.62, H 4.42, N 6.12.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH:24]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:29]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:30]2=[O:31])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=NC1CCCC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(C3CCCC3)c(=O)n(C3CCCC3)c12
Yield: 44.8 %

Procedure:
1,3-Dicyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (17 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and cyclopentyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 380 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.51 (s, 1H), 7.82 (d, 1H), 7.62 (t, 1H), 7.28 (d, 1H), 5.34 (m, 1H), 4.98 (m, 1H), 4.15 (s, 3H), 3.95 (m, 4H), 2.38 (m, 2H), 2.12 (m, 2H), 1.93-1.98 (m, 2H), 1.58-169 (m, 4H), and 1.38 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:31][CH3:32])#[N:2].[OH-:33].[Na+].Cl>CS(C)=O>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:31][CH3:32])(=[O:33])[NH2:2]
Reactant: [OH-]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1C#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1C(N)=O
Reaction time: 2 h

Procedure:
N-(4-[(7-cyano-6-methoxy-4-quinolyl)oxy]phenyl)-N′-(4-fluorophenyl)urea (43 mg) in 1.5 ml of dimethylsulfoxide at 80° C., a 5N aqueous NaOH solution was added thereto and the mixture was heated and stirred for 2 hours. The reaction solution was neutralized with 1N HCl and the precipitated crystals were filtered out and washed with ethanol to obtain 17 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:27][C:26]=3[CH3:28])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 62–64° C.; 1H NMR (300 MHz, CDCl3): δ 6.92 (s, 1 H), 6.67 (s, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 5.02–4.92 (m, 1 H), 4.38 (t, J=7.7 Hz, 2 H), 3.79 (s, 3 H), 3.66 (dd, J=10.3, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.6 Hz, 1 H), 3.36 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.90–1.70 (m, 2 H), 0.94 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C19H25N3O3Cl (M+H)+: 378.1584; Found m/z 378.1604.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]#[N:11])C(OCC)=O)#[N:2].N1C=CC=CC=1.F[B-](F)(F)F.[C:23]1([N+:29]#[N:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[C:23]1([N:29]=[N:30][CH:3]([CH2:9][C:10]#[N:11])[C:1]#[N:2])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(C#N)CC#N
Reactant: N#[N+]c1ccccc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CO
Product: N#CCC(C#N)N=Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
A solution of ethyl 2,3-dicyanopropanoate (1.58 g, 10.38 mmol) in methanol (52 mL) and pyridine (2.52 mL, 31.14 mmol) was cooled to 10° C. in an ice bath. Benzenediazonium tetrafluoroborate was added portion-wise over 20 minutes at 10° C. and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and partitioned between DCM and water. The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound (2.8 g, 28%). The crude product was taken on directly to the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]([CH3:17])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]([CH3:17])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Cl:21])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc(OC(C)Cc2ccc(CO)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OC(C)Cc2ccc(CCl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of {4-[2-(4-methylphenoxy)propyl]phenyl}methanol (0.725 g) in THF (20 mL) were added CCl4 (2.3 mL) and PPh3 (1.640 g) at room temperature under an Ar atmosphere. The mixture was heated at reflux for 6.5 hours, and then cooled to room temperature, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1) to afford 1-[4-(chloromethyl)phenyl]propan-2-yl 4-methylphenyl ether (0.696 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1>>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of 0.70 g (3.0 mmol) 4-(3-chloropyridin-2-yl)benzoic acid and 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine in 10 mL polyphosphoric acid was stirred for 5 min and irradiated for 15 min with microwaves in a microwave reactor (Initiator Sixty, Biotage). After cooling to room temperature, 20 mL distilled water was added to the solution which was then adjusted to a neutral pH value with NaOH. The precipitates thus obtained was filtered and separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.72 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH2:18])[S:15][C:5]=2[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.C(N(C(C)C)C(C)C)C.[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>ClCCCl.C1COCC1>[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:18][C:16]2[S:15][C:5]3[C:6]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)=[N:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=3[N:17]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a stirred suspension of 150 mg (0.56 mmol) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine in 3 ml 1,2-dichloroethane and 3 ml THF at room temperature were added 0.29 ml (1.69 mmol) N-ethyldiisopropylamine and 117 mg (0.62 mmol) 4-(chloromethyl)benzoyl chloride and stirring continued at 80° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 157 mg (67%) 4-chloromethyl-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-benzamide as a yellow solid. ES-MS m/e (%):421 (M{37Cl}+H+, 35), 419 (M{35Cl}+H+, 100).
Reaction SMILES: OC1C=[CH:6][C:5]([C:8]2[C:18]3[N:17]4[C:13](=[CH:14][CH:15]=[CH:16]4)[C:12](=[O:19])[C:11]=3[S:10][CH:9]=2)=[CH:4][C:3]=1OC.[C:22]([O:25][C:26](=[O:28])[CH3:27])(=O)[CH3:23].[C:29](O)(=[O:31])C>>[C:26]([O:25][C:22]1[CH:6]=[C:5]([C:8]2[C:18]3[N:17]4[C:13](=[CH:14][CH:15]=[CH:16]4)[C:12](=[O:19])[C:11]=3[S:10][CH:9]=2)[CH:4]=[CH:3][C:23]=1[O:31][CH3:29])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: COc1cc(-c2csc3c2-n2cccc2C3=O)ccc1O
Product: COc1ccc(-c2csc3c2-n2cccc2C3=O)cc1OC(C)=O

Procedure:
The procedure is as in Example 18, using the compound of Example 24 as substrate and carrying out the reaction in acetic acid in the presence of acetic anhydride.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH:11](Br)Br)=[CH:7][C:6]=2[C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[C:4]([F:26])[CH:3]=1.S(=O)(=O)(O)[OH:28]>O>[Cl:1][C:2]1[C:10]2[O:9][C:8]([CH:11]=[O:28])=[CH:7][C:6]=2[C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[C:4]([F:26])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C(Br)Br)cc23)c1=O
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C=O)cc23)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
0.29 g (0.56 mmol) of 3-(7-chloro-2-dibromomethyl-5-fluorobenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was added to 15 ml of sulfuric acid, followed by stirring at 50° C. for 1 hour. Then, the mixture was poured into water and extracted with diethyl ether. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.20 g (yield: 96%) of the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.O>CN1C(=O)CCC1>[F:29][C:19]([F:18])([F:28])[C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:6]2[C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:24][CH:25]=1
Reactant: Cc1cccc2c3c([nH]c12)CCN(C)C3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc2c3c(n(CCc4ccc(C(F)(F)F)nc4)c12)CCN(C)C3
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1.0 mmol) in NMP (2.5 ml), powdered KOH (561 mg, 10 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (346 mg, 2.0 mmol) was added slowly to the above solution and stirred for 16 h at 25 deg C. After completion of the reaction (monitored by LCMS), water (5 mL) was added to the crude and extracted with the ethyl acetate. The organic layer was dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 40 mg (8.2%) of 5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole as TFA salt.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C@:8]2([C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[O:13][C@H:12]([C:21]([NH2:23])=[O:22])[CH2:11]2)[NH:7][C:6]1=[O:24].[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C@:8]3([C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[O:13][C@H:12]([C:21]([NH2:23])=[O:22])[CH2:11]3)[NH:7][C:6]2=[O:24])[CH2:28][CH2:27]1
Reactant: NC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCCl)C2=O)c2cc(F)ccc2O1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCN3CCC(O)CC3)C2=O)c2cc(F)ccc2O1
Temperature: 80 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
A mixture of (2S,4S)-1'-(3-chloropropyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (Reference Example 2, 15.0 g, 42.2 mmol), 4-hydroxypiperidine (8.52 g, 84.4 mmol), K2CO3 (7.00 g, 50.7 mmol) and N,N-dimethylformamide (100 ml, 1.29 mol) was stirred for 5 hours at 80° C. After distilling off the solvent, the residue was chromatographed on silica gel, eluted with CH2Cl2 /MeOH/NEt2 (5/1/1), and recrystallized from AcOEt/MeOH to give prism crystals of the desired compound (16.2 g, 91.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:5]=2)[CH:18]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-amino-5-bromo-benzotrifluoride (17.1 g, 71.24 mmol), 4-methylimidazole (17.6 g, 213.72 mmol), potassium carbonate (9.8 g, 71.24 mmol), cupper (1.1 g, 17.81 mmol), and cupper iode (II) (3.4 g, 17.81 mmol) were added to N,N-dimethylacetamide (100 ml) at room temperature, and mixed therewith at 140˜150° C. for 16 hr. After the reaction was completed, the temperature of the reaction vessel was cooled to RT. Then, ethyl acetate (200 ml) was added thereto and mixed therewith for 30 min. The reaction mixture was filtered with Celite, and an organic layer of the filtered solution was washed with water, dried with magnesium sulfate, distilled under vacuum, and washed with n-hexane to give the titled compound as pale white solid.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[C:8]([C:13]#[N:14])=[N:9][CH:10]=[CH:11][CH:12]=1.S(=O)(=O)(O)[OH:16].[OH-].[Na+]>C(O)(=O)C.O>[C:1]([NH:14][C:13]([C:8]1[C:7]([CH3:6])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1C#N
Reactant: CC(C)(C)O
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccnc1C(=O)NC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
111 g (1.5 mol) of tert.-butanol and 118 g (1 mol) of 3-methyl-2-cyanopyridine in 100 ml of glacial acetic acid are initially taken. 147 g of sulphuric acid (100% strength) are added dropwise to this mixture at 50° C. in the course of 0.5 hours, and the mixture is stirred for 3 hours at 50° C. The oil is stirred into 1,000 ml of water, and the resulting solution is adjusted to pH 7 with concentrated sodium hydroxide solution, while cooling with ice. The oil which separates out is separated off, taken up in methylene chloride and extracted by shaking with water. The organic phase is dried over sodium sulphate, evaporated down and distilled. 166.5 g (86.7% of theory) of 3-methylpyridine-2-carboxylic acid N-tert.-butylamide are obtained as a viscous oil of boiling point 155° C./4 mbar.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C4C=CC([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:44][C:45]([F:54])([F:53])[CH:46]([C:48]1[N:49]=[CH:50][S:51][CH:52]=1)[OH:47]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:24])[O:47][CH:46]([C:48]4[N:49]=[CH:50][S:51][CH:52]=4)[C:45]([F:44])([F:53])[F:54])[CH2:16][CH2:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCC1CCN(c2cccc(-c3ccc(F)cc3)n2)CC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC(c1cscn1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC1CCN(c2cccc(-c3ccc(F)cc3)n2)CC1)OC(c1cscn1)C(F)(F)F
Yield: 47.2 %

Procedure:
The procedure described in Example 4 (step 4.6.) is followed. Starting from 0.183 g (1 mmol) of 4-nitrophenyl 2-[6′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylcarbamate, described in Example 4 (step 4.4.), 0.19 g (1.5 mmol) of N,N-diisopropylethylamine, 0.006 g (0.05 mmol) of N,N-dimethylaminopyridine and 0.51 g (1.1 mmol) of 2,2,2-trifluoro-1-thiazol-4-ylethanol, obtained in step 5.1., and after chromatography on silica gel, eluting with a 40/60 mixture of ethyl acetate and cyclohexane, followed by recrystallization from a mixture of diethyl ether and hexane, gives 0.240 g of pure product in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[C:11]([OH:18])[CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN1CCOCC1.[N:41]([CH2:44][CH2:45][NH2:46])=[N+:42]=[N-:43]>O.CN(C)C=O>[N:41]([CH2:44][CH2:45][NH:46][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:10][C:11]=1[OH:18])=[O:17])=[N+:42]=[N-:43]
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2F)cc1O
Reactant: [N-]=[N+]=NCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: [N-]=[N+]=NCCNC(=O)c1ccc(-c2ccc(F)cc2F)cc1O
Temperature: 0 °C
Yield: 60.7 %

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stir bar was added 2′,4′-difluoro-3-hydroxybiphenyl-4-carboxylic acid (0.301, 1.20 mmol), N,N-Dimethylformamide (5 mL), N,N′-Dicyclohexylcarbodiimide (0.248 g, 1.20 mmol) and n-methylmorpholine (0.25 mL). The reaction mixture was cooled to 0° C. and allowed to stir. Then, 2-azidoethanamine (0.1037 g, 1.20 mmol) was added dropwise and allowed to slowly warm to room temperature while stirring for 24 hr. The reaction mixture was diluted with water, extracted with dichloromethane, washed with 1N HCl, washed with saturated sodium bicarbonate, washed with brine and then concentrated de vacuo. The resulting residue was then purified via silica gel column chromatography (1:40 methanol:dichloromethane to 1:10 methanol:dichloromethane) to give N-(2-azidoethyl)-2′,4′-difluoro-3-hydroxybiphenyl-4-carboxamide (0.232 g, 61% yield). 1H NMR (300 MHz, CDCl3) δ 7.60 (s, 1H), δ 7.47 (d, 1H), δ 7.29 (m, 2H), δ 7.02 (d, 1H), δ 6.88 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.3, 160.8, 135.1, 131.3, 131.2, 131.3, 131.2, 126.8, 118.8, 114.6, 112.0, 111.8, 104.8, 104.6, 104.3, 50.7, 39.3 ppm; HRMS (ESI) calcd for C15H12F2N4O3 (M+) 318.0928. found 318.0933.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C:16]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][CH:13]1[C:22]([O:24]CC)=[O:23])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C:16]2([CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:15][CH2:14][CH:13]1[C:22]([OH:24])=[O:23])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CCOC(=O)C1CCC2(CCOCC2)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C(C(=O)O)CCC12CCOCC2)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.4 %

Procedure:
To a solution of ethyl 1-{N-[(methyloxy)carbonyl]-L-valyl}-8-oxa-1-azaspiro[4.5]decane-2-carboxylate (167) (80 mg, 0.2 mmol) in THF/water/methanol (1.0 mL/0.5 mL/0.5 mL) was added lithium hydroxide monohydrate (13 mg, 0.3 mmol) and the reaction stirred at room temperature for 72 h. The reaction was treated with 1N HCl (0.5 mL) and the reaction partitioned between EtOAc and 0.1 N HCl. The organic layer was separated and dried over MgSO4 and concentrated in vacuo to afford the title compound as a white solid (53 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br. s., 1H) 7.45-7.61 (m, 1H) 4.89-5.03 (m, 1H) 3.70-3.87 (m, 2H) 3.65 (t, J=9.2 Hz, 1H) 3.53 (s, 3H) 3.02 (td, J=12.9, 4.9 Hz, 1H) 2.71-2.90 (m, 1H) 2.22-2.38 (m, 1H) 1.87-2.19 (m, 3H) 1.53-1.73 (m, 1H) 1.32-1.42 (m, 1H) 1.06-1.15 (m, 1H) 0.61-0.98 (m, 8H). LC-MS ESI (M+H)+=342.95.